Intensive care unit (ICU)-acquired muscle atrophy and weakness are key contributors to post-intensive care syndrome (PICS), which can lead to long-term functional impairments. Although the ICU survival rate has improved, many patients continue to experience persistent functional impairments that hinder their reintegration into society. This review summarizes a series of observational and interventional studies conducted as part of the Muscle Atrophy Zero Project, focusing on the etiology, assessment, and prevention of ICU-acquired muscle atrophy and weakness. The project findings highlight the critical role of inflammation, particularly neutrophil infiltration, in the pathogenesis of muscle atrophy. Muscle damage can be assessed using ultrasound, bioelectrical impedance analysis, and urinary titin. Among them, ultrasound demonstrates high diagnostic accuracy for detecting low muscularity, and urinary titin has emerged as a promising biomarker of muscle degradation. Preventive strategies include early rehabilitation, neuromuscular electrical stimulation, vibration therapy, and nutritional support, especially protein supplementation. These multimodal interventions have shown efficacy in mitigating ICU-acquired muscle atrophy and weakness. However, follow-up systems for PICS remain underdeveloped. A continual multimodal intervention approach that combines physical rehabilitation with nutritional therapy is essential. The development of structured follow-up programs is vitally needed to confront the long-term challenges posed by PICS.